Translational medicine in inborn errors of metabolism and other rare genetic diseases

Research summary:

Inborn errors of metabolism (IEM) are a large group of rare genetic diseases, including any condition in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Nevertheless many of them detected by standard biochemical test are not genetically solved. In addition, many of them lack a definitive therapy. In this context, our objectives, aligned with the worldwide aims in translational research in rare diseases, are addressed to improve the knowledge of IEM towards tailored treatments. First, our activity is aimed to the identification of new genes causing pathology using a combination of "omics" tools (genomic, transcriptomic and metabolomic technologies) and cellular biology techniques, in order to decipher the effect of altered genes and to identify novel pathological processes. Specifically, we are working on the identification and characterization of genetic defects involved in the process of glycosylation and protein transport (CDG syndrome), as well as in other diseases related to mitochondrial dysfunction or neurological disorders due to cerebral glucose transport deficiency, among others. We are also involved in the development of specific therapeutic strategies targeted to the mechanism of action of the mutations detected in neurometabolic diseases in the era of the personalized medicine. To that end, we are specifically involved in the development of therapies designed to rescue defects affecting protein folding, an extended mechanism in many IEM. For preclinical studies and for searching additional therapeutic targets based on pathophysiology studies we are working in the generation of disease cellular models obtained from reprogramming of patient derived fibroblasts and subsequent differentiation into hepatocytes, neurons or other tissues more relevant to the disease. In a later preclinical stage we intend also to use hepatic and cerebellar organoids to validate the potential drugs before testing in the adequate animal models.

This project is funded by the following grants: ISCIII (PI16/00573), CIBERER (ER18TRL746), Comunidad de Madrid (B2017/BMD3721) y Fundación Isabel Gemio in collaboration with La Obra Social de la Caixa (LCF/PR/PR16/11110018).

Image
Image

* For external calls please dial 34 91196 followed by the extension number
Last name Name Laboratory Ext.* e-mail Professional category
Bravo Alonso Irene 220 4596/7830 ibravo(at)cbm.csic.es Ayudante Investigación
Bartolomé Espinosa Alejandro 220 4596 Estudiante TFG
Gallego Martínez Diana 220 4596/7830 Titulado Sup.de Actividades Técn. y Profes. GP1
Gámez Abascal Alejandra 220 4596/7830 agamez(at)cbm.csic.es Profesor Contratado Universidad, GA
Leal Pérez Mª Fátima 220 4566/7830 fleal(at)cbm.csic.es Contratado CIBER
Navarrete López de Soria Rosa María 220 4566/7830 rnavarrete(at)cbm.csic.es Contratado CIBER
Pérez González Belén 220 4566/7830 bperez(at)cbm.csic.es Profesor Titular Universidad, GA
Rodríguez Pombo Pilar 220 4628 mprodriguez(at)cbm.csic.es Profesor Titular Universidad, GA
Soriano Alejandro 220 4560/7830
Vilas Lagoa Alicia 220 4560/7830 alicia.vilas(at)cbm.csic.es Titulado Sup.de Actividades Técn. y Profes. GP1

Relevant publications:

  • Bravo-Alonso I, Navarrete R, Vega AI, Ruíz-Sala P, García Silva MT, Martín-Hernández E, Quijada-Fraile P, Belanger-Quintana A, Stanescu S, Bueno M, Vitoria I, Toledo L, Couce ML, García-Jiménez I, Ramos-Ruiz R, Martín MÁ, Desviat LR, Ugarte M, Pérez-Cerdá C, Merinero B, Pérez B, Rodríguez-Pombo P. “Genes and Variants Underlying Human Congenital Lactic Acidosis-From Genetics to Personalized Treatment”. J Clin Med. 2019 Nov 1;8(11). pii: E1811. doi: 10.3390/jcm8111811.
  • Arribas-Carreira L, Bravo-Alonso I, López-Márquez A, Alonso-Barroso E, Briso-Montiano Á, Arroyo I, Ugarte M, Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P, Richard E. "Generation and characterization of a human iPSC line (UAMi005-A) from a patient with nonketotic hyperglycinemia due to mutations in the GLDC gene”. Stem Cell Res. 2019 Aug;39:101503. doi: 10.1016/j.scr.2019.101503.
  • Navarrete R, Leal F, Vega AI, Morais-López A, Garcia-Silva MT, Martín-Hernández E, Quijada-Fraile P, Bergua A, Vives I, García-Jiménez I, Yahyaoui R, Pedrón-Giner C, Belanger-Quintana A, Stanescu S, Cañedo E, García-Campos O, Bueno-Delgado M, Delgado-Pecellín C, Vitoria I, Rausell MD, Balmaseda E, Couce ML, Desviat LR, Merinero B, Rodríguez-Pombo P, Ugarte M, Pérez-Cerdá C, Pérez B. “Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program”. Eur J Hum Genet. 2019 Apr;27(4):556-562. doi: 10.1038/s41431-018-0330-0.
  • Coughlin CR 2nd, Swanson MA, Kronquist K, Acquaviva C, Hutchin T, Rodríguez-Pombo P, Väisänen ML, Spector E, Creadon-Swindell G, Brás-Goldberg AM, Rahikkala E, Moilanen JS, Mahieu V, Matthijs G, Bravo-Alonso I, Pérez-Cerdá C, Ugarte M, Vianey-Saban C, Scharer GH, Van Hove JL. “The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT”. Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Erratum in: Genet Med. 2018 Jan 04
  • Ortigoza-Escobar JD, Alfadhel M, Molero-Luis M, Darin N, Spiegel R, de Coo IF, Gerards M, Taylor RW, Artuch R, Nashabat M, Rodríguez-Pombo P, Tabarki B, Pérez-Dueñas B; Thiamine Deficiency Study Group. “Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors”. Ann Neurol. 2017 Sep;82(3):317-330. doi: 10.1002/ana.24998.
  • García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjós M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agulló SB. “Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients”. Hum Mutat. 2014 Apr;35(4):470-7. doi: 10.1002/humu.22513.
  • Oyarzabal A, Martínez-Pardo M, Merinero B, Navarrete R, Desviat LR, Ugarte M, Rodríguez-Pombo P. “A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease”. Hum Mutat. 2013 Feb;34(2):355-62. doi: 10.1002/humu.22242.
  • New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. BBA, Molecular Basis of Disease(2018) 1864(2):640-648.
  • Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type. Stem Cell Research (2018) 29:143-147.
  • Protein misfolding diseases: prospects of pharmacological treatment. Clin Genet. 2017 Jul 3. doi: 10.1111/cge.13088. Review.
  • A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis. J Pediatr. 2017 Apr;183:170-177.
  • Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease. Hum Mutat. 2017 Jun;38(6):678-691. doi: 10.1002/humu.23208. Epub 2017 Mar 20.
  • Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. Hum Mutat. 2017 Feb;38(2):160-168. doi: 10.1002/humu.23138. Epub 2016 Nov 21.

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: